Cholestyramine is a high molecular weight, cationic polymer which binds anionic bile acids in the gastrointestinal tract and prevents their reabsorption. Since cholestyramine is neither degraded nor absorbed, it causes bile acids with which it binds to be excreted. This cholestyramine-induced loss of bile acids from the enterohepatic bile acid pool stimulates the liver to replenish the supply via synthesis de novo from cholesterol thereby reducing hepatic intracellular cholesterol. Subsequently, synthesis of hepatic high affinity receptors for apolipoprotein B is stimulated to sequester low density lipoproteins from the plasma to replenish intracellular cholesterol levels since low density lipoproteins are comprised largely of cholesterol. This is the cascade of events which causes plasma cholesterol to be reduced by the binding of bile acids to cholestyramine in the gastrointestinal tract.
Even more important is that cholestyramine selectively reduces the "bad" cholesterol (low density lipoprotein cholesterol) that causes atherosclerosis (C. E. Day, In "Low Density Lipoproteins", edited by C. E. Day and R. S. Levy, Plenum Press, New York, pp. 421-438, 1976). Consequently, cholestyramine eventually inhibits development of atherosclerotic lesions by binding to bile acids in the intestine. Furthermore, atherosclerosis is the primary cause for heart attacks and sudden cardiac death. So, ultimately, the simple act of sequestering bile acids in the gut by cholestyramine leads to a significant reduction not only in plasma cholesterol and low density lipoproteins but also to reductions in morbidity and mortality from cardiovascular disease (JAMA 251: 351-374, 1984), which is the leading cause of death in the U.S.
In addition to its proven efficacy for reducing cardiovascular morbidity and mortality, cholestyramine also has an excellent record of safety (JAMA 251:351-374, 1984). Since the polymer is neither degraded nor absorbed in the intestinal tract, it exhibits no systemic toxicities. Because of its proven record of both safety and efficacy and its well understood mechanism of action, it is not unreasonable to regard cholestyramine as a cure for atherosclerotic disease (C. E. Day, In "The Cholesterol Connection", Artery Press, Fulton, pp. 99-107, 1987) if it were appropriately utilized by patients with elevated cholesterol levels.
Although possessing several very meritorious therapeutic properties, cholestyramine also possesses several handicaps which have precluded widespread implementation of prophylactic and therapeutic administration of this drug for the prevention and treatment of atherosclerotic cardiovascular disease. Patient compliance in the long-term administration of cholestyramine is relatively poor (JAMA 251: 351-374, 1984). People find it objectionable to adhere to prolonged administration of cholestyramine for several reasons.
One shortcoming which contributes to poor patient compliance is the lack of potency with the recommended daily dose being 4 to 24 grams per day. The drug also has an objectionable taste and odor. Additionally, the physical form of the drug is a tiny plastic bead which has a gritty mouthfeel. Because of the bulk which must be consumed, among other factors, cholestyramine may cause in many patients a number of uncomfortable gastrointestinal side effects such as bloating, nausea, constipation, or gas. For patients in whom constipation may be a barrier to consumption of cholestyramine, many physicians recommend concurrent administration of a bulk laxative such as psyllium hydrocolloid. Although aiding in the relief or prevention of constipation, this simply requires the patient to now consume two instead of one bulky gritty material.
Cholestyramine was originally marketed under the brand name Cuemid(.RTM.), essentially as the pure bulk drug which could be stirred in a glass of water, fruit juice, or other appropriate liquid, and consumed. However, the smell and taste of the bulk drug is so objectionable (the malodorous component being trimethylamine, one of the essential fragrances of rotten fish) that Cuemid(.RTM.) had very low patient acceptance. This taste and odor was successfully masked with flavors and sweeteners in the Questran(.RTM.) formulation which currently is the market standard.
The Questran(.RTM.) formulation, or any other presently-available formulation, does not successfully address the problem of the objectionable gritty nature of cholestyramine. However, several attempts have been made unsuccessfully to create palatable compositions. One such attempt is reported in U.S. Pat. No. 3,974,272 in which the composition is comprised of an aqueous medium (water, milk, or fruit juice), cellulosic material, alginate, and cholestyramine. A similar approach to conceal the grittiness is described in European Patent Application EP 251,369 in which a combination of cholestyramine, antimicrobial agent, suspending agent, and coating agent is used to improve the palatability of the resin. European Patent Application EP 177,368 describes a hydrophobic matrix consisting of fatty acids, natural or synthetic waxes or mixtures thereof, and a glyceride, which helps to physically mask the unpleasant taste of cholestyramine. In a similar vein European Patent Application EP 227,603 describes a chewable drug delivery system in which cholestyramine is coated with lecithin or glycerides or polyalkylene glycols and a confectionary matrix to improve the palatability of the drug. U.S. Pat. No. 4,565,702 coats insoluble fiber with soluble fiber such as pectin or alginate. German Offen. 2,344,090 describes a cholestyramine-containing coacervate comprised of cholestyramine, modified cellulose, lactose and flavor to mask the grittiness and improve taste characteristics of the drug. An ingestible aggregate and delivery system is detailed in U.S. Pat. No. 4,747,881 in which the cholestyramine bead is coated with a preswelled hydrocolloid and dried to form aggregates of coated beads in which hydration is delayed. These aggregates can be ingested and chewed so that prehydration is not required as in formulations of cholestyramine such as Questran(.RTM.) U.S. Pat. No. 4,404,346 and Canadian Patent 1,150,212 describe a process for comminution of cholestyramine beads to produce a powder which forms stable dispersions and does not have a gritty taste.
All previous attempts to overcome the grittiness problem with cholestyramine and similar gritty drugs have one underlying characteristic. Each has been an attempt to physically conceal, alter, mask, eliminate, or modify the gritty nature and texture of the drug. The nature of the present invention is to capitalize on the gritty characteristic of cholestyramine and similar gritty drugs to create a formulation which is not only acceptable to the patient but pleasant as well.